2. Academic Validation
  3. Integrative Mendelian randomization and experimental validation unveil novel druggable targets in primary biliary cholangitis

Integrative Mendelian randomization and experimental validation unveil novel druggable targets in primary biliary cholangitis

  • Eur J Pharmacol. 2026 Apr 10:1020:178775. doi: 10.1016/j.ejphar.2026.178775.
Yinling Li 1,  Huanhuan Xie 2,  Zhenjie Zhuang 2,  Xin Fang 3,  Wenjun Yang 4,  Yan Luo 5,  Jiangyi Hu 2,  Wei Wang 2,  Haitao Wang 6,  Xiaobing Dou 7,  Junping Shi 8,  Jin Yang 9
Affiliations

Affiliations

  • 1 Department of Translational Medicine Center, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China; Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Hangzhou, Zhejiang, China; Department of School of Life Sciences, Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310053, China.
  • 2 Department of Translational Medicine Center, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China; Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Hangzhou, Zhejiang, China.
  • 3 Department of Translational Medicine Center, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China.
  • 4 Department of Pathology, The Affiliated Hospital of Hangzhou Normal University, Hangzhou, China.
  • 5 Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Hangzhou, Zhejiang, China.
  • 6 William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK.
  • 7 Department of School of Life Sciences, Zhejiang University of Traditional Chinese Medicine, Hangzhou, Zhejiang, 310053, China; Zhejiang-Hong Kong Joint Laboratory of Liver and Spleen Simultaneous Treatment in Traditional Chinese Medicine, Zhejiang, 310053, China.
  • 8 Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Hangzhou, Zhejiang, China; Department of Liver Disease, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China. Electronic address: [email protected].
  • 9 Department of Translational Medicine Center, Hangzhou Normal University Affiliated Hospital, Hangzhou, Zhejiang, China; Institute of Hepatology and Metabolic Diseases, Hangzhou Normal University, Hangzhou, Zhejiang, China. Electronic address: [email protected].
PMID: 41819524 DOI: 10.1016/j.ejphar.2026.178775
Abstract

Background: Primary Biliary Cholangitis (PBC) is a progressive autoimmune liver disorder characterized by immune-mediated bile duct destruction, leading to cirrhosis and liver failure. Current first-line therapy with ursodeoxycholic acid (UDCA) exhibits suboptimal efficacy in 30-40% of patients, underscoring the urgent need for novel therapeutic targets.

Methods: We employed a druggable genome-wide Mendelian randomization (MR) framework integrating blood/liver cis-eQTLs, pQTLs, and PBC GWAS meta-analysis. Bayesian colocalization and phenome-wide MR (Phe-MR) validated causal relationships and off-target effects. Protein-protein interaction (PPI) networks and transcriptomic profiling elucidated biological mechanisms. Drug repurposing via DSigDB and molecular docking prioritized compounds, with efficacy validated in ANIT-induced cholestasis models and human PBC biopsies.

Results: MR analysis identified 14 druggable genes causally associated with PBC risk, with replication in the FinnGen cohort confirming CD58 and IL7R as tier-1 targets. Functional studies revealed both genes modulate immune synapse formation and T-cell homeostasis, supported by significant hepatic overexpression in human PBC biopsies. Molecular docking prioritized PHA-00665752 and monorden as high-affinity Binders. In vivo validation demonstrated that PHA-00665752 significantly attenuated ANIT-induced cholestasis.

Conclusions: This study establishes CD58 and IL7R as mechanistically grounded therapeutic targets for PBC. We provide a translational framework integrating causal genomics, computational drug screening, and experimental validation by demonstrating their protective effects against cholestatic bile duct injury, thereby informing therapy development for PBC.

Keywords

Cholestasis; Colocalization; Druggable genes; Mendelian randomization; Primary biliary cholangitis.

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